Project Summary The overall objective of this proposal is to provide a rigorous research and training experience for Dr. Ronak Lakhia to become an independent physician scientist. The applicant is a board certified nephrologist who recently completed post-doctoral training as a NIH-T32 fellow in an independently funded laboratory. She plans to enhance her skillset and build on her experience to become an excellent physician scientist and a nationally recognized expert in autosomal dominant polycystic kidney disease (ADPKD) and metabolism. The objectives of this proposal are designed to make new scientific insights and allow the applicant to grow and reach her full potential through proper mentorship. She will study the effects of disrupting microRNA (miRNA) mediated regulation of peroxisome proliferator activated receptor alpha (Ppara) in ADPKD. The studies she has proposed have the potential to provide profound new insights on the metabolic reprogramming that occurs in ADPKD. UT Southwestern is a world renowned institution with a proven track record in performing cutting- edge research, providing excellent resources, and training successful young faculty to become leaders in their respective fields. The candidate has developed a comprehensive career development plan to complement her research aims. The candidate's training aims include 1) metabolic phenotyping 2) gene editing and 3) statistics/bioinformatics. Her co-mentors complement each other perfectly to properly guide and monitor the candidate's research experience and training. Dr. Steven Kliewer, a member of the National Academy of Sciences, is a world renowned expert in nuclear hormone receptors and metabolism. Dr. Vishal Patel, Assistant Professor in Nephrology, is an international expert in miRNAs and ADPKD. In addition, Dr. Chao Xing, Associate Professor and Director of the McDermott Bioinformatics Core at UT Southwestern, will serve an advisory role for the applicants training in statistics/bioinformatics. An advisory committee consisting of 4 exemplary scientists and physician scientists will provide additional support and mentorship for career development. The applicant will determine whether preventing miRNAs from binding to the Ppara 3'-UTR enhances its translation, improves oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO), and attenuates cyst growth in ADPKD. She has developed a unique set of tools to precisely address each of her specific aims. Aim 1 will determine whether deletion of miRNA binding sites from Ppara 3'-UTR normalizes its expression and slows cyst growth. Aim 2 will determine whether deletion of miRNA binding sites from Ppara 3'-UTR improves OXPHOS/FAO. Aim 3 will determine whether Ppara 3'-UTR Target Site Blockers can stabilize its expression and slow cyst growth. Together these studies will establish Ppara 3'-UTR as a drug target for ADPKD and provide proof-of-principle for targeted stabilization of mRNA transcripts as a novel therapeutic approach.